CLINICAL OUTCOMES AND TREATMENT COURSE OF EYES WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION FOLLOWING THE DEVELOPMENT OF ENDOPHTHALMITIS.

PURPOSE: To evaluate the clinical course of patients with neovascular age-related macular degeneration (nAMD) after developing endophthalmitis during their treatment with intravitreal injections. METHODS: Multicenter, retrospective series. RESULTS: From April 2013 to October 2018, 196,598 intravitreal anti-vascular endothelial growth factor (VEGF) injections were performed, with 75 cases of endophthalmitis (incidence 0.0381%). There was no association between intravitreal anti-VEGF drug (P = 0.29), anesthetic method (P = 0.26), povidone concentration (P = 0.22), or any intraprocedure variable and endophthalmitis incidence. Seventy-two patients (96%) were treated with intravitreal tap and inject , while 3 underwent immediate pars plana vitrectomy. After endophthalmitis resolution, 17 patients (22.7%) were not re-treated for nAMD (in 10 cases due to inactive disease; follow-up, 115 ± 8.4 weeks). Patients required less frequent anti-VEGF injections after infection (7.4 ± 0.61 weeks vs. 11.5 ± 1.8 weeks; P = 0.004). Preinfection logarithm of the minimum angle of resolution visual acuity was 0.585 ± 0.053 (∼20/77). It worsened with endophthalmitis (1.67 ± 0.08, ∼20/935; P < 0.001) and again on postendophthalmitis treatment day 1 (1.94 ± 0.064; count fingers; P < 0.001), but improved after reinitiating nAMD therapy (1.02 ± 0.11; ∼20/209; P < 0.001). Better visual acuity on postendophthalmitis week 1 (P = 0.002) and reinitiation of nAMD treatment (P = 0.008) were associated with better final visual acuity, and streptococcal culture with worse visual acuity (P = 0.028). The postendophthalmitis treatment interval was associated with the anti-VEGF drug used (aflibercept = ranibizumab > bevacizumab; P < 0.001). CONCLUSION: Patients with nAMD required fewer injections after endophthalmitis, suggesting a biological change in disease activity. Neovascular age-related macular degeneration became quiescent in 13.3% of eyes. Most achieved better outcomes with anti-VEGF reinitiation.

Endophthalmitis in Eyes Treated with the Port Delivery System with Ranibizumab: Summary of Cases during Clinical Trial Development.

PURPOSE: The Port Delivery System with ranibizumab (PDS) is approved in the United States for neovascular age-related macular degeneration. The United States Prescribing Information has a Boxed Warning for endophthalmitis and reports the incidence rate in patients developing endophthalmitis after receiving the PDS compared with monthly intravitreal ranibizumab. Endophthalmitis cases noted in the Boxed Warning, treatment outcomes, potential contributing factors, and potential mitigations are summarized. DESIGN: Retrospective review of endophthalmitis cases in PDS-treated patients in the phase II Ladder (NCT02510794) and phase III Archway (NCT03677934) and Portal (NCT03683251) trials. PARTICIPANTS: Endophthalmitis cases in the pooled all-PDS safety population (N = 555) including PDS patients in Ladder, Archway, or Portal. METHODS: Ladder patients received PDS (10, 40, or 100 mg/ml) with pro re nata refill-exchanges. Archway patients received PDS 100 mg/ml with fixed refill-exchanges every 24 weeks (PDS Q24W). Portal patients received PDS Q24W from day 1. MAIN OUTCOME MEASURES: Clinical features, management, and visual outcomes were summarized. Cases were summarized by date of PDS implant and/or refill, other prior invasive procedures/refills, and preceding/concurrent conjunctival complications. RESULTS: Twelve endophthalmitis events were reported in 11 patients (11/555 [2.0%]) through March 12, 2021. All were cultured (3 were culture positive) and treated with intravitreal antibiotics. Two cases (2/555 [0.4%]) occurred in the immediate postoperative period (days 5 and 6). Nine cases occurred later (day range: 57-853), including 4 before the first refill-exchange (day range: 57-161). Five patients received between 1 and 11 refill-exchanges before the event (onset: 6-168 days after last refill-exchange). Seven cases (7/11 [63.6%]) had preceding/concurrent conjunctival complications. At last follow-up, 7 patients recovered vision to study baseline levels or ≥20/40; 4 patients experienced vision loss of ≥15 ETDRS letters. CONCLUSIONS: Endophthalmitis is a serious complication that can endanger vision after any ocular procedure, including PDS implantation. Most, but not all, of this limited series of endophthalmitis cases were late onset, associated with conjunctival breach, and recovered vision with treatment. Meticulous attention to PDS surgical techniques with vigilant monitoring of conjunctiva during follow-up may minimize risk of endophthalmitis. Prompt treatment is critical for optimizing patient outcomes. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Evaluation of injection frequency and visual acuity outcomes for ranibizumab monotherapy in exudative age-related macular degeneration.

OBJECTIVE: To evaluate the visual outcomes for intravitreal ranibizumab administered on an as-needed basis for exudative age-related macular degeneration (AMD) and to investigate the relationship between injection frequency and visual outcome in this setting. DESIGN: Retrospective, interventional case series. PARTICIPANTS: A total of 131 eyes with treatment-naïve, exudative AMD undergoing ranibizumab monotherapy. METHODS: Intravitreal ranibizumab was administered on an as-needed basis guided by clinical examination and optical coherence tomography (OCT). The OCT scans were evaluated by the treating physicians for the presence of intraretinal fluid, subretinal fluid, intraretinal cysts, or increasing pigment epithelial detachment size. Clinical data including visual acuity (VA), choroidal neovascularization lesion morphology, and treatment course were collected retrospectively for analysis. MAIN OUTCOME MEASURES: Mean change in best-corrected Snellen VA. RESULTS: The mean age was 81.3 years, mean follow-up was 12+/-4.3 months (minimum 6 months, median 12 months), and mean number of injections was 5.2+/-2.8. Mean baseline Snellen VA for the entire population was 20/110 and significantly improved at 6 months (20/80; P = 0.0002) and at last follow-up (20/90; P = 0.0066). At 6 months, 31% of eyes had gained at least 3 lines of VA and 90.5% had avoided loss of 3 lines. On average, it took 3.0 injections and 3.5 months to achieve a "dry" or "flat" macula on OCT after initiating treatment. Resolution of intra- and subretinal fluid on OCT did not correlate with the degree of vision improvement. Eyes receiving more frequent injections (defined as <2 months mean inter-injection interval) gained more vision (+2.3 lines at 6 months) than eyes receiving injections less frequently (+0.46 lines at 6 months; P = 0.012). At 6 months, 3.1% of those in the more frequent injection group lost >3 lines of vision compared with 15.9% in the >2 months interval group (P = 0.011). CONCLUSIONS: In a population receiving as-needed injections of ranibizumab for exudative AMD, visual improvement was related to the frequency of injections received but not to the resolution of fluid by OCT. Treatment with ranibizumab on a strictly as-needed basis may result in undertreatment and significantly less visual gain. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Hemorheologic abnormalities associated with HIV infection: altered erythrocyte aggregation and deformability.

PURPOSE: To investigate possible alterations of erythrocyte aggregation and deformability, which are factors that can influence blood flow, in human immunodeficiency virus (HIV)-infected individuals and to determine whether these factors are related to the severity of immunodeficiency. METHODS: Laboratory evaluations were performed on 46 HIV-infected individuals and 44 HIV-negative control subjects. Current and nadir (lowest previous) CD4+ T-lymphocyte counts were identified for each subject. Erythrocyte aggregation was measured using a fully automatic erythrocyte aggregometer. Factors related to erythrocyte aggregation were also determined: erythrocyte sedimentation rate (ESR), zeta sedimentation ratio (ZSR), and plasma fibrinogen levels. Erythrocyte deformability was observed at various fluid shear stress levels, with a laser diffraction ektacytometer. Correlations were sought between each of these measures and current or nadir CD4+ T-lymphocyte counts, and each measure was compared between three subgroups based on current and nadir CD4+ T-lymphocyte counts (severely immunosuppressed, immune reconstituted, never severely immunosuppressed). RESULTS: The following parameters were significantly different between HIV-infected subjects and controls: increased erythrocyte aggregation, at stasis (P < 0.001) and low shear stress (P < 0.001), increased ESR (P < 0.001), increased ZSR (P < 0.028), increased serum fibrinogen (P = 0.015), and decreased erythrocyte deformability (P < 0.001). Only erythrocyte aggregation at stasis correlated significantly with current CD4+ T-lymphocyte count (r = - 0.344, P = 0.022). None of the parameters was significantly different between HIV-infected subgroups. CONCLUSIONS: Increased aggregation and decreased deformability of erythrocytes are associated with HIV-infection regardless of the severity of immunodeficiency. HIV-infected individuals may be at risk for progressive retinal microvascular damage from persistent hemorheologic abnormalities, despite immune reconstitution associated with potent antiretroviral drug therapies.

Hemorheologic abnormalities associated with HIV infection: in vivo assessment of retinal microvascular blood flow.

PURPOSE: To evaluate retinal microvascular blood flow in human immunodeficiency virus (HIV)-infected individuals using scanning laser Doppler flowmetry (SLDF) and to seek correlations between flow and various laboratory measures that may predict alterations in flow. METHODS: The Heidelberg Retina Flowmeter and SLDF software were used to acquire in vivo retinal blood flow data from 24 HIV-infected individuals and 16 HIV-negative control subjects. In each subject, separate scans were performed in each of six retinal regions: nasal parapapillary retina; macula; and the superior, nasal, inferior, and temporal periphery. Erythrocyte aggregation (assessed in vitro by a fully automatic erythrocyte aggregometer and by zeta sedimentation ratio [ZSR, a hematocrit-independent sedimentation rate]), serum fibrinogen level, plasma viscosity, and leukocyte rigidity (assessed in vitro with a cell transit analyzer) were compared with flow in selected regions. RESULTS: Flow was significantly higher in the periphery (superior, nasal, inferior, temporal) than in the posterior retina (nasal parapapillary retina, macula). Flow was highest in the temporal periphery for both HIV-infected subjects and control subjects. Flow in the posterior retina was significantly lower in HIV-infected subjects than in control subjects (P < 0.0001). Among HIV-infected individuals, flow in the macula correlated negatively with ZSR (r = -0.397, P = 0.0547) and leukocyte rigidity (r = -0.505, P = 0.0119). CONCLUSIONS: Microvascular blood flow in the posterior retina is reduced in HIV-infected individuals. Both increased erythrocyte aggregation and increased leukocyte rigidity contribute to this hemorheologic abnormality.

T3JAM, a novel protein that specifically interacts with TRAF3 and promotes the activation of JNK(1).

Previous studies suggest that localization of tumor necrosis factor receptor (TNFR)-associated factor (TRAF) family members is important for regulating their signal transduction. During a screen for TRAF3-associated proteins that potentially alter TRAF3 subcellular localization and enable signal transduction, we identified a novel protein, T3JAM (TRAF3-interacting Jun N-terminal kinase (JNK)-activating modulator). This protein associates specifically with TRAF3 but not other TRAF family members. Coexpression of T3JAM with TRAF3 recruits TRAF3 to the detergent-insoluble fraction. More importantly, T3JAM and TRAF3 synergistically activate JNK but not nuclear factor (NF)-kappaB. Our studies indicate that T3JAM may function as an adapter molecule that specifically regulates TRAF3-mediated JNK activation.

Intravitreal injection of ranibizumab for foveal-macular pattern dystrophy: case report.

In the recent years, anti-angiogenic medications have successfully treated other diseases associated with choroidal neovascularization. The anti-angiogenic therapy alone or combined with LASER and/or steroids has been effective in controlling ocular neovascularization, not only restricted to the treatment of typical membranes due to macular degeneration in the wet form. The discovery and subsequent use of these drugs has revolutionized medicine and ophthalmology. This report illustrates an example of successful treatment in a challenging pathology where it was found important visual and anatomical response after the use of ranibizumab.

Verteporfin photodynamic therapy of six eyes with retinal capillary haemangioma.

PURPOSE: Single-centre consecutive interventional case series by retrospective chart review to evaluate the efficacy of verteporfin (Visudyne™) photodynamic therapy (PDT) of retinal capillary haemangioma (RCH). METHODS: Following an initial period of observation, six eyes of five patients with RCH (juxtapapillary 3 and extrapapillary (EP) 3) received 1-3 sessions of standard verteporfin PDT upon the development of progressive vision-threatening complications. Four of the five patients had von Hippel-Lindau (VHL) disease. Follow-up included documentation of best-corrected Snellen visual acuity (BCVA), tumour regression, and presence or absence of subretinal fluid (SRF) and/or lipid exudation as assessed by dilated fundus examination (DFE), fundus photos, and optical coherence tomography (OCT). These parameters were documented at 1 week, 1 month, and 3 months following each PDT session and up to 32 months following the first PDT. RESULTS: All eyes showed favourable response to PDT as defined by tumour regression or stabilization as well as improvement of SRF and lipid exudation. BCVA improved or stabilized in three eyes. Three eyes required PDT retreatment for recurrent SRF. Epiretinal membrane (ERM) worsened in three eyes, requiring vitreoretinal surgery at a median of 6 months following PDT. CONCLUSIONS: PDT is a moderately effective treatment for juxtapapillary and EP RCH. In this series, PDT resulted in tumour regression or stabilization as well as in the improvement of SRF and lipid exudation in all cases. However, stabilization or improvement of visual acuity was observed in only 50 per cent of the cases. The treatment benefits may be limited by pre-existing macular changes and worsening of ERM. A larger prospective study is necessary to validate these findings.

Intravitreal injection of ranibizumab for foveal-macular pattern dystrophy: case report / Injeção intravítrea de ranibizumabe para distrofia foveal-macular em padrão: relato de caso

In the recent years, anti-angiogenic medications have successfully treated other diseases associated with choroidal neovascularization. The anti-angiogenic therapy alone or combined with LASER and/or steroids has been effective in controlling ocular neovascularization, not only restricted to the treatment of typical membranes due to macular degeneration in the wet form. The discovery and subsequent use of these drugs has revolutionized medicine and ophthalmology. This report illustrates an example of successful treatment in a challenging pathology where it was found important visual and anatomical response after the use of ranibizumab.

Nos últimos anos, os medicamentos antiangiogênicos têm tratado com sucesso outras doenças relacionadas com a neovascularização da coroide. A terapia antiangiogênica isoladamente ou combinada com LASER e/ou esteroides têm se mostrado eficaz no controle da neovascularização ocular, não se restringindo apenas ao tratamento das membranas típicas da degeneração macular na forma úmida. A descoberta e o posterior uso destas drogas vêm revolucionando a medicina e a oftalmologia. Este relato ilustra um exemplo de tratamento de sucesso numa patologia desafiadora onde se obteve importante resposta visual e anatômica após uso do ranibizumabe.

Cooperation of multiple signaling pathways in CD40-regulated gene expression in B lymphocytes.

CD40/CD40L interaction is essential for multiple biological events in T dependent humoral immune responses, including B cell survival and proliferation, germinal center and memory B cell formation, and antibody isotype switching and affinity maturation. By using high-density microarrays, we examined gene expression in primary mouse B lymphocytes after multiple time points of CD40L stimulation. In addition to genes involved in cell survival and growth, which are also induced by other mitogens such as lipopolysaccharide, CD40L specifically activated genes involved in germinal center formation and T cell costimulatory molecules that facilitate T dependent humoral immunity. Next, by examining the roles of individual CD40-activated signal transduction pathways, we dissected the overall CD40-mediated response into genes independently regulated by the individual pathways or collectively by all pathways. We also found that gene down-regulation is a significant part of the overall response and that the p38 pathway plays an important role in this process, whereas the NF-kappa B pathway is important for the up-regulation of primary response genes. Our finding of overlapping independent control of gene expression modules by different pathways suggests, in principle, that distinct biological behaviors that depend on distinct gene expression subsets can be manipulated by targeting specific signaling pathways.

IRF3 mediates a TLR3/TLR4-specific antiviral gene program.

We have identified a subset of genes that is specifically induced by stimulation of TLR3 or TLR4 but not by TLR2 or TLR9. Further gene expression analyses established that upregulation of several primary response genes was dependent on NF-kappaB, commonly activated by several TLRs, and interferon regulatory factor 3 (IRF3), which was found to confer TLR3/TLR4 specificity. Also identified was a group of secondary response genes which are part of an autocrine/paracrine loop activated by the primary response gene product, interferon beta (IFNbeta). Selective activation of the TLR3/TLR4-IRF3 pathway potently inhibited viral replication. These results suggest that TLR3 and TLR4 have evolutionarily diverged from other TLRs to activate IRF3, which mediates a specific gene program responsible for innate antiviral responses.